Derivatives of the 2-(lower alkyl)-3-(lower alkyl)-4-aryl-3-or 4-cyclo-hexenecarbinols

ABSTRACT

COMPOUNDS OF THE GENERAL FORMULA   1-(R&#39;&#39;-COO-CH2-),2-R&#34;,3-R&#34;&#39;&#39;,4-(R-PHENYL)CYCLOHEX-3- OR 4-   ENE   ARE DISCLOSED WHEREIN -R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HYDROXY, LOWER ALKOXY OF UP TO 8 CARBON ATOMS, LOWER ALKYL OF UP TO 8 CARBON ATOMS, AND LOWER ALKYL ANILINO OF UP TO 4 CARBON ATOMS; -R&#39;&#39; IS SELECTED FROM THE GROUP CONSISTING OF ALKYL AND ALKENYL OF UP TO 20 CARBON ATOMS, CYCLOALKYL LOWER ALKYL OF UP TO 3 CARBON ATOMS IN THE ALKYL PORTION, ADAMANTYL, PYRIDYL, FURYL, LOWER ALKYL CARBOXYLIC ACIDS AND THEIR ALKALI METAL SALTS, ESTERS AND CARBAMATES; AND R&#34; AND R&#34;&#39;&#39; ARE SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL OF UP TO 3 CARBON ATOMS. THESE COMPOUNDS EXHIBIT ESTROGENIC PROPERTIES AND WHEN GIVEN IN A SINGLE SUBCUTANEOUS DOSE HAVE LONG ACTING EFFECTS IN THE SUPPRESSION OF ANIMAL REPRODUCTION.

United States Patent 3,816,507 DERIVATIVES OF THE 2 (LOWER ALKYL)-3- (LOWER ALKYI.) 4 ARYL 3 0R 4-CYCLO- HEXENECARBINOLS George Karmas, Bound Brook, N.J., assignor to Ortho Pharmaceutical Corporation No Drawing. Original application May 14, 1968, Ser. No. 728,900, now Patent No. 3,557,129. Divided and this application Sept. 14, 1970, Ser. No. 72,218

Int. Cl. C07c 69/74 U.S. Cl. 260-468 R 7 Claims ABSTRACT OF THE DISCLOSURE Compounds of the general formula are disclosed wherein -R is selected from the group consisting of hydrogen, hydroxy, lower alkoxy of up to 8 carbon atoms, lower alkyl of up to 8 carbon atoms, and lower alkyl anilino of up to 4 carbon atoms; R is selected from the group consisting of alkyl and alkenyl of up to 20 carbon atoms, cycloalkyl lower alkyl of up to 3 carbon atoms in the alkyl portion, adamantyl, pyridyl, furyl, lower alkyl carboxylic acids and their alkali metal salts, esters and carbamates; and R" and R' are selected from the group consisting of lower alkyl of up to 3 carbon atoms. These compounds exhibit estrogenic properties and when given in a single subcutaneous dose have long acting effects in the suppression of animal reproduction.

III RI! CH O- IC-R' wherein R is selected from the group consisting of hydrogen, hydroxy, lower al-koxy of up to 8 carbon atoms, lower alkyl of up to 8 carbon atoms, and lower alkyl anilino of up to 4 carbon atoms; R is selected from the group consisting of alkyl and alkenyl of up to 20 carbon atoms, cycloalkyl lower alkyl of up to 3 carbon atoms in the alkyl portion, adamantyl, pyridyl, furyl, lower alkyl carboxylic acids and their alkali metal salts, esters and carbamates; and R" and R" are selected from the group consisting of lower alkyl of up to 3 carbon atoms.

The compounds of the present invention are related to the compounds disclosed in U.S. Pat. 3,344,147 and in my copending patent applications, Ser. Nos. 662,310; 662,311; 662,295; and 560,116. The compounds of the patent and of my copending patent applications are known to possess activity as agents for the suppression of reproduction when fed orally to animals. The compounds of the present invention are active as suppressants of reproduction not only upon oral administration but also when given parenterally and some of the compounds of the present invention can suppress reproduction over a long period of time when given in only one subcutaneous injection.

These compounds are all esters of 2-(lower alkyl)-3- (lower alkyl)4-phenylcyclohexenecarbinol and analogs of the same and therefore may be prepared generally by the esterification of the appropriate carbinol with acids (R'COOH), acid halides (R'COCl), acid anhydrides (R'COOOCR) and ketenes In addition, the compounds may be prepared by the mono-acetylation of the primary-tertiary diol with subsequent dehydration according to the following reaction CHzO COR in! H @Gomo COR I {TI I RI! The following examples illustrate the preparation of some of the compounds of the invention. While only one method of preparation is disclosed for each compound, it is to be understood that any of the other methods noted above can also be utilized.

ALKYL ESTERS (1) R=hydrogen or lower alkyl The starting material for Examples I through V I is (2-methyl-3-ethyl-4-phenyl 4 or 3-cyclohexenyl-1-)- methanol which is suitably prepared as described in U.S. 'Pat. 3,344,147.

EXAMPLE I (2-Methy1-3ethy1-4-phenyl-3cyclohexenyl- 1 methyl acetate EXAMPLE II (2-Mcthyl-3-ethyl-4-phenyl-3-cyclohexenyl-1) methyl caproate A solution of 4 g. of the M-cyclohexenylcarbinol in 15 ml. of dry pyridine is stirred at 0-5 C. while 1% molecular equivalents of caproyl chloride is added. The resulting pasty mixture is stirred at 25 C. for 15 minutes, heated at 95 C. for 15 minutes, and then cooled. Five ml. of water is added and the mixture stirred vigorously for 2 hours. After dilution with m1. of ether, the ether phase is washed twice with cold 5% hydrochloric acid to remove pyridine, and then twice with cold 5% sodium 3 I hydroxide. The ether solution is then dried and evaporated. The residual oil is developed on a column of alumina (neutral, W-I) prepared in benzene-hexane. Elution with benzene and ether aifords the ester free of alcohol and carboxylic acid. The oily ester is distilled under high vacuum to afford the purified product, an oil which boils at 138-140 C. at .002 mm.

Calcd. for C H O C, 80.44; H, 9.83. Found: C, 80.25; H, 9.81.

M 5.76, 8.01, 8.51, 9.07, 9.92, 13.14, 14.22 1 (neat).

EXAMPLE III (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl octanoate This compound is prepared following the procedure of Example II and using octanoyl chloride. The compound is an oil which boils at 150-155 C. at .001 mm.

Calcd. for C H O C, 80.85; H, 10.18. Found: C, 80.66; H, 10.28.

M 5.74, 8.56, 9.01, 11.79, 13.14, 14.25 1 (neat).

EXAMPLE IV (2-Methyl-3 -ethyl-4-phenyl-4-cyclohexenyl- 1 methyl eicosanoate Using eicosanoyl chloride and again following the procedure of Example II and recrystallizing the crude solid ester from hexane (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)-methyl eicosanoate is prepared in the form of white flakes having a melting point of 47-48 C.

Calcd. for C H O C, 82.38; H, 11.52. Found: C, 82.25; H, 11.38.

M 5.74, 8.62, 11.88, 13.21, 13.90, 14.22 (KBr).

EXAMPLE V (2-Methyl-3ethyl-4-phenyl-4-cyclohexenyl-1 )methyl Z-ethylhexanoate A mixture of 2.0 g. of (2-Methyl-3-ethyl-4-phenyl-4- cyclohexenyl-1)methanol and 6.3 ml. of a 20% solution of butylethyl ketene in toluene is held for one hour at 25 C. and then for one hour at 100 C. After the addition of methanol to destroy excess ketene, the toluene solution is evaporated and the oily residue is chromatographed on alumina (benzene-hexane elution) to isolate the crude ester. The ester is then further purified by two distillations to yield 1.7 g. of a colorless mobile oil which boils at 150-154 C. at .001 mm.

Calcd. for C H O C, 81.76; H, 10.29. Found: C, 81.16; H, 10.24.

M 5.77, 8.52, 8.71, 10.00, 11.80, 13.17, 14.28 1 (neat).

Any alkyl ester of the basic carbinol can be prepared by selecting the proper acid, acid chloride, acid anhydride or ketene. The A or A analog is prepared by utilizing the appropriate carbinol.

EXAMPLE VI (2-Methyl-3-ethy1-4phenyl-4-cyclohexenyl- 1 methyl benzoate This compound is prepared using benzoyl chloride in the procedure of Example II. It is a colorless viscous oil which boils at 180-185 C. at .001 mm.

Calcd. for C H O C, 82.59; H, 7.84. Found: C, 82.38; H, 7.71.

M 5.81, 7.85, 9.00, 9.32, 9.72, 11.81, 13.18, 14.0 1 (neat).

EXAMPLE VII [2-Methyl-3ethyl-4- (m-tolyl) -4-cyclohexenyl-1 methyl octanoate This compoond is formed from [2-Methyl-3-ethyl-4- (m-tolyl)-4-cyclohexenyl-1]methanol and octanoyl chloride following the procedure of Example II. The carbinol starting material is prepared in the manner described in my copending application Ser. No. 662,311.

The compound is a pale yellow oil which boils at 155- 165 C. at .001 mm.

Calcd. for C H O C, 81.03; H, 10.34. Found: C, 81.05; H, 10.36.

M 5.77, 8.58, 9.03, 11.81, 12.83, 14.19 2 (neat).

Esters having other lower alkyl substitution in the meta position in the phenyl ring may be prepared following the same procedure of Example II from the appropriate carbinol. The ortho and para analogs also may be prepared following this same procedure. The starting carbinols for the latter are prepared as described in the above-noted copending application and my copending application Ser. No. 662,310.

(2) R=lower alkoxy EXAMPLE VIII [2-Methyl-3-ethyl-4-(o-anisyl)-4-cyclohexenyl-1]methyl hexanoate To a stirred solution of 3.1 g. of 2-Methyl-3-ethyl-4- hydroxy 4 (o-anisyl) cyclohexanecarboxylic acid (the preparation of which is disclosed in my copending appli cation Ser. No. 662,295) in ml. of tetrahydrofuran is added cautiously 4.0 g. of lithium aluminum hydride. The reaction mixture is refluxed with stirring for one hour and then hydrolyzed in a large volume of ice and water. After acidification with dilute hydrochloric acid, the mixture is filtered, the filter cake being washed Well with ether and water. Organic products in the filtrate are separated by extracting twice with ether; and the combined ether solution is then washed with dilute sodium hydroxide, dried and evaporated. The ether residue is distilled to afford 3.0 g. of a pale yellow glass having a boiling point of -145 C. at .001 mm. This is the 1,4- diol: [2-Methyl-3-ethyl-4-hydroxy-4-(o-anisyl) cyclohexanyl-1]methanol.

Calcd.: C, 73.34; H, 9.41. Found: C, 73.20; H, 9.53.

m 2.92, 8.10, 9.70, 11.00, 12.51, 13.24,. (KBr).

A solution of 2.6 g. of the 1,4-diol, described above, and 6 ml. of hexanoic anhydride in 20 ml. of pyridine is heated at 85 C. for 1% hours, 2 ml. of water added and heating continued at 85 C. for /2 hour more. The solution is diluted with hexane and the hexane solution is washed with water, twice with dilute hydrochloric acid, and twice with dilute potassium carbonate. After drying and evaporation of the hexane solution, the oily residue is distilled to afford 3.0 g. of a yellow oil having a boiling point of -165" C. at .001 mm. This is the ester-monoalcohol: [2-Methyl-3-ethyl-4-hydroxy-4-(o-anisyl) cyclohexanyl-11methyl hexanoate.

Calcd.: C, 73.36; H, 9.64. Found: C, 74.32; H, 9.76. m 2.83, 5.78, 8.10, 8.50, 9.70, 12.51, 13.23,. (neat).

A solution of 1.0 g. of the ester-monoalcohol and 4 ml. of boron trifluoride etherate in 20 ml. of ether is held at 20-25 C. for 5 hours and then further diluted with ether and washed twice with aqueous potassium carbonate. The ether solution is dried and evaporated and the oily residue is distilled to aflord 0.8 g. of [2-Methyl3- ethy1-4-(o-anisyl)-4-cyclohexenyl-1]methyl hexanoate, a yellow oil'which boils at 140-145 C. at .001 mm.

Calcd: C, 77.05; H, 9.56. Found: C, 76.86; H, 9.39.

M 5.75, 8.02, 8.50, 11.82, 13.2811 (neat).

Other esters of the o-anisyl series can be prepared by selecting the proper acid anhydride. In forming the psubstituted esters the starting carbinol is suitably formed according to the procedures disclosed in my copending application Ser. No. 560,116.

(3) R=hydroxyl and acyloxy EXAMPLE IX [2-Methyl-3 -ethyl-4- p-acetoxyphenyl) -4-cyclohexenyl- 1]methyl acetate To a stirred solution of 4.0 g. of 2-methyl-3-ethy1-4-(phydroxyphenyl)-4-cyclohexenecarboxylic acid (prepared as described in my copending application Ser. No.

560,116) in 250 m1. of tetrahydrofuran is added cautiously 7.0 g. of lithium aluminum hydride. The thick mixture is stirred at 20-25 C. for 20 hours and then it is hydrolyzed in a large volume of ice and water. After the mixture has been acidified with dilute hydrochloric acid, it is filtered and the filter cake is washed thoroughly with ether and water. The organic products in the filtrate are separated by two extractions with ether and then the combined ether solution is washed twice with aqueous potassium bicarbonate, dried, and evaporated to a solid residue. The latter is recrystallized from ether to afford 2.5 g. of white prisms which melt at 166-167 C. This is the carbinol, [2-Methyl-3-ethyl-4-(p-hydroxyphenyl)-4-cyclohexenyl-l ]methanol.

Calcd. for C H 'O C, 78.01; H, 9.00. Found: C, 78.01; H, 9.06.

AA 2.92, 6.61, 8.00, 8.17, 9.97, 11.76, 12.10;; (KBr).

A solution of 1.5 g. of the carbinol and 7.0 ml. of acetic anhydride in 20 ml. of pyridine is heated at 70 C. for /2 hour and then it is hydrolyzed in ice plus water. The hydrolysis mixture is extracted twice with ether and the combined ether solution is washed twice with dilute hydrochloric acid and then with aqueous potassium bicarbonate. After drying and evaporation of the ether solution, the oily residue is distilled to afford 1.6 g. of [2- Methyl 3-ethyl-4-(p-acetoxyphenyl)-4-cyclohexenyl-l3- methyl acetate, a colorless oil which boils at 135-140" C. at .001 mm.

Calcd. for C H O C, 72.70; H, 7.93. Found: C, 72.44; H, 8.00.

M 5.68, 5.74, 7.30, 8.33, 9.68, 9.80, 10.97, 11.83 (neat).

Other di-esters of the para-hydroxy phenyl carbinols may be prepared by selecting the proper acid chloride.

EXAMPLE X [2-Methy1-3 -ethyl-4- (p-hydroxyphenyl) -4-cyclohexenyl- 1]methyl acetate This and other hydroxy derivatives are obtained from the appropriate di-esters which are in turn prepared as described in Example IX.

A mixture of 1.0 g. of the diacetate, 0.8 g. of potassium bicarbonate, ml. of water, and 17 ml. of methanol is refluxed for five minutes and then diluted with cold water. The organic material is extracted with an etherhexane mixture which is dried and evaporated to an oily residue which slowly crystallizes. This crude monoacetate is recrystallized from hexane containing 5% ether to afford 0.5 g. of [2-Methyl-3-ethyl-4-(p-hydroxyphenyD-L cyc1ohexeny1-1]methyl acetate in the form of white prisms which melt at 67-72 C.

Calcd. for C H O C, 74.97; H, 8.39. Found: C, 75.74; H, 8.68.

M 2.89, 5.81, 6.61, 7.90, 9.68, 11.76, 11.91;]. (KBr).

EXAMPLE XI [2-Methyl-3-ethyl-4- (p-isobutyryloxyphenyD-4- cyclohexenyl-l methyl acetate Where the acyloxy group is different from the ester group, the compound is produced fiom the p-hydroxyphenyl mono ester obtained as described in Example X.

A solution of 0.35 g. of the phenolic monoacetate and 2.5 ml. of isobutyric anhydride in m1. of pyridine is held at 25 C. for 3 hours and then hydrolyzed by stirring with water for one hour. The product is extracted with hexene and the hexane solution is washed with dilute hydrochloric acid and with potassium carbonate. After drying and evaporation of the hexane solution, the residue is distilled to afford 0.35 g. of [2-Methyl-3-ethyl- 4 (p isobutyryloxyphenyl) 4-cyclohexenyl-1]methyl acetate, a colorless oil which boils at 145-150 C. at .001 mm.

6 Calcd. for C H O C, 73.71; H, 8.44. Found: C, 73.58; H, 8.48.

M 5.70, 5.75, 8.10, 8.31, 8.57, 8.81, 9.69, 10.90, 11.48, 11.80;; (neat).

(4) R: anilino EXAMPLE XII [2-Methyl-3-ethyl-4-(p-dimethylanilino)-3 and 4- cyclohexenyl-l -methy1 valerate This compound is prepared from 2-methyl-3-ethyl-4- (p-dimethylanilino)-3 and 4-cyclohexenecarboxylic acid which is prepared as described in my copending patent application 662,3 1 1.

To a stirred solution of 3.0 g. of the inseparable mixture of 2-methyl-3-ethyl-4-(p-dimethylanilino)-3- and 4- cyclohexenecarboxylic acids in ml. of tetrahydrofuran is added cautiously 3.0 g. of lithium aluminum hydride. The mixture is stirred at 25 C. for 20 hours and then it is hydrolyzed in a large volume of ice and water. This hydrolysis mixture is filtered and the filter cake is washed thoroughly with ether. The product is isolated by two extractions of the filtrate with ether and the combined ether solution is dried and evaporated. The oily ether residue is distilled to afford 2.5 g. of a very .viscous yellow oil which boils at -145 C. at .001 mm. This is the carbinol mixture, [2 Methyl 3 ethyl-4-(p-dimethylanilino)-3 and 4-cyclohexenyl-1]methanol.

Calcd. for CmHzqONZ C, 79.07; H, 9.95. Found: C, 79.08; H, 9.91.

M 2.99, 6.20, 6.59, 7.40, 9.42, 9.70, 9.91, 10.58, 12.29 (neat).

A solution of 1.0 g. of the mixed carbinol described above and 20 ml. of pyridine is stirred and cooled in an ice bath while 3 ml. of valeryl chloride is added. The dark mixture is held at 20 for 3 hours and then it is hydrolyzed by stirring with water and hexane for one hour. The hexane layer is separated and is washed twice with dilute sodium hydroxide, dried, and evaporated. The oily residue is developed onto a chromatographic column of neutral alumina, and elution with ether affords the crude ester. Distillation of the ester gives the mixture of [2 Methyl 3 ethyl-4-(p-dimethylanilino)-3 and 4- cyclohexenyl-1]methyl valerate as a yellow oil which boils at l60165 C. at .001 mm.

Calcd. for C H O N: C, 77.26; H, 9.07. Found: C, 77.82; H, 9.95.

M 5.77, 6.20, 6.59, 7.41, 8.57, 10.56, 1228p. (neat).

ADAMANTOATE ESTERS EXAMPLE XIH (2-Methyl-3 -ethyl-4-phenyl-3 -cyclohexenyl-1 methyl l-adamantoate This compound is prepared from (2-Methyl-3-ethyl-4- phenyl-3-cyclohexenyl-1)methanol and adamantoic acid chloride following the procedure of Example II.

Calcd. for C27H35O2I C, 82.60; H, 9.24. Found: C, 82.37; H, 9.41.

M 5.80, 8.07, 8.45, 9.25, 13.19, 14.28, 14.74, (KBr).

M.P. 75-76 C.

EXAMPLE XIV [2-Methyl-3-ethyl-4-(p-anisyl)-4-cyclohexenyl-1] methyl l-adamantoate This compound is prepared from [2-Methyl-3-ethyl-4- (p-anisyl) 4 cyclohexenyl-l1methanol and adamantoic acid chloride following the procedure of Example II. It is a viscous oil which boils at 200-220" C. at .002 mm.

Calcd. for C H O C, 79.58; H, 9.06. Found: C, 79.23; H, 9.09.

M 5.80, 8.0l-8.l2, 8.42, 9.02, 9.24, 9.60, 11.93, l3.50,u (neat).

7 CYCLOALKYL LOWER ALKYL ESTERS EXAMPLE XV [2-Methyl-3-ethyl-4 (p-anisyl -3 -cyclohexenyl- 1] methyl fl-cyclopentylpropiouate This compound is formed from cyclopentylpropionic acid chloride and [2-Methyl-3-ethyl-4-(p-anisyl)-3-cyclohexenyl-1]methanol according to the procedure of Example II. The compound is an oil which boils at 160-170 C. at .001 mm.

Calcd. for C25H3503: C, H, 9.44. Found: C, 78.04; H, 9.49.

M 5.75, 8.01, 8.49, 9.61, l2.04,u. (neat).

NMR (CDCI 0.73, 0.84, 0.96, 0.90, 1.01.

FUROATES AND NICOTINATES EXAMPLE XVI (2-Methyl-3-ethyl-4-phenyl-4- cycl ohexenyl- 1 methyl nicotinate This compound is prepared using nicotinoyl chloride following the procedure of Example II but omitting the HCl washing. It is a yellow oil which boils at 175-180 C. at .001 mm.

Calcd. for C H O N: C, 78.77; H, 7.51. Found: C, 78.54; H, 7.57.

M 5.79, 7.78, 8.81, 8.95, 9.73, 11.80, 13.15, 13.50, 14.27n (neat).

EXAMPLE XVII (2-Methy1-3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl 2-furoate This compound is prepared generally following the procedures of Example II and using 2-furoyl chloride to afford white granules which melt at 70-72 C.

Calcd. for C H ,O C, 77.75; H, 7.46. Found: C, 77.81; H, 7.54.

M 5.86, 7.70, 8.56, 9.00, 11.83, 12.92, 13.17, 14.30 2 (KBr).

OTHER MISCELLANEOUS ESTERS OF THE CAR- BINOLS INCLUDING ESTERS WITH DIBASIC ACIDS, UNSATURATED ACIDS, ETC.

EXAMPLE XVIII (Z-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1 methyl hemisuccinate solution of 3.1 g. of the carbinol and 9.0 g. of suc- CllllC anhydride in 60 ml. of pyridine is heated at 90- 95 C. for one hour, then 9 ml. of water is added and heating is continued for minutes longer. The mixture is diluted with hexane and the hexane solution washed four times with water to remove succinic acid, dried and evaporated. Distillation of the oily residue aifords 3.4 g. of the hemisuccinate, a viscous colorless oil which boils at 180-190 C. at .001 mm.

Calcd. for C H O C, 72.70; H, 7.93. Found: C, 72.61; H, 8.05.

(neat).

EXAMPLE XIX (2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl succinamate 1.0 g. of the compound of Example XVIII and 8 ml. of thionyl chloride is refluxed for minutes, diluted with 20 ml. of toluene, and evaporated to afford an oily residue of the ester acid chloride. The latter is dissolved in 20 ml. of cold dioxane and this solution is treated with 4 ml. of 28% aqueous ammonia. After a period of 1% hours at 20 C. this reaction mixture is diluted with water and extracted with ether. The ether solution is washed with water, dried and evaporated. The residue is recrystallized from ether to afford 0.68 g. of the ester amide, white prisms which melt at 90-91 C.

8 Calcd. for C20H2703NI C, 72.92; H, 8.26. Found: C, 72.77; H, 8.44.

M :2.95, 3.11, 5.78, 5.97, 7.42, 8.49, 10.12, 11.88, 13.20, 14.23/J- (KBr).

EXAMPLE XX (2-Methy1-3-ethyl-4-phenyl-4-cyclohexenyl-1 methyl ethyl succinate Ah 5.77, 8.60, 9.72, 11.70, 11.80, 13.16, 14.27;; (neat). No. 16857 COHEN, A. 5-16-74-Day Mach. l0

EXAMPLE XXI (Z-Methyl-3-cthyl-4-phenyl-3 -cyclohexenyl-l methyl succinate This compound is prepared utilizing succinyl chloride and following the procedure of Example II. The product is purified by chromatography on alumina to yield a yellow oil.

Calcd. for C H O C, 79.66; H, 8.54. Found: C, 80.61; H, 9.06.

M 5.75, 8.60, 9.96, 10.13, 13.17, 14.27, (neat).

EXAMPLE XXII (2-Methyl-3-ethyl-4-phenyl-3-cyclohexenyl-1)methyl 10-undecenoate This compound is prepared using undecenoyl chloride and following the general procedure of Example II to yield a colorless oil which boils at -180 C. at .001

Calcd. for C H O C, 81.76; H, 10.17. Found: C, 81.68; H, 10.23.

' M 5.75, 8.52, 10.00, 11.00, 13.18, 14.27/L (neat).

While the preparation of only some of the compounds of this invention has been specifically described, one skilled in the art should be able to prepare the remainder of the compounds following the general techniques set forth.

As mentioned previously, the compounds of this invention exhibit anti-littering effects when given orally or parenterally and are estrogenic agents to varying degrees.

Estrogenic elfects are measured against the estrogenic eifects of estradiol as a standard. In carrying out the test, female rats of a Wistar-derived strain are bilaterally ovariectomized under light ether anesthesia. About a Week following surgery all animals are given a priming dose of 2-10 ,ug. estradio1-17 3 by subcutaneous injection and vaginal smears are taken on each of the next two days. Animals which do not show vaginal cornification are rested a week and reprimed. Rats which respond positively to the priming injection are rested a week and then given a single subcutaneous injection of the test material in sesame oil. Vaginal smears are taken daily to assess the duration of estrogenic response (vaginal cornification) in each animal as opposed to the vaginal cornification induced by the priming. The results, tabulated in Table I, for certain of the compounds prepared according to the examples hereinbefore set out show that the compounds of this invention have substantially estrogenic activity.

The parenteral anti-littering properties of the compounds are measured by administering to adult female rats of Wistar-derived strain a single subcutaneous injection of the test material in sesame oil. Controls receive sesame oil vehicle only. Ordinarily twenty animals are assigned to each group.

Both groups are cohabitated with adult male rats in the ratio of 3 males per 5 females starting on the day of treatment. Rats are examined twice weekly for gross signs of pregnancy. Gravid animals are removed and allowed to deliver so that a count of young and their condition may be recorded. The mean interval between drug administration (and cohabitation) and conception is calculated for each group using an average gestation length of 21 days.

Cohabitation is continued for 90 days or until 80% of the females become pregnant, whichever occurs sooner.

The minimum dosage in mg./kg. body weight required to prevent littering in the rats for various compounds, the preparation of which was specifically described in the examples, is set out in Table I. The actual effect of some of the compounds on littering at various dosage levels is set out in Table II.

10 What is claimed is: 1. Compounds of the formula wherein -R is selected from the group consisting of hydrogen, hydroxy, lower alkoxy of up to 8 carbon atoms, lower alkyl of up to 8 carbon atoms, and lower alkyl amino of up to 4 carbon atoms; R is cyclopentyl lower alkyl of up to 3 carbon atoms in the alkyl portion, or adamantyl, and R" and R are selected from the group consisting of lower alkyl of up to 3 carbon atoms.

2. Compounds of claim 1 wherein R is adamantyl. 3. (2-methyl-3-ethyl-4-phenyl-3-cyclohexenyl-1)methyl l-adamantoate of claim 2.

TABLE I B 011.0 O-R' Pharmacological activity Anti-littering Estrogenie parenteral R A (times EE) (mg.)

OH; 3 CH1 4 2.4 -2-5 C5H11 3 1/4 --C5H11 4 -C1H15 4 1.7 1 -C1nH:0 4 0.50

can, 4 0.70 -2.5

- H-CAHO -C1H15 4 0.20 CaHs 4 1.2 5 -C5H11 4 0.07

X p-OH CH1 4 XL. p-OCCH(CHa)z CH| 4 -04H@ 3 & 4 0.001 Adamantyl-l 3 1.2 1 Adamantyl-l 4 2/3 1 2. 5 Adamantyl-l 4 4/3 1 i 3 2 CHzCH1- Pyridy1-3 4 H Furyl-Z 4 H -CHCH2CONH1 4 xxn H (CH2)1CH=CH2 4 l 290 da.

TABLE I 4. (2-methyl-3-ethyl-4-phenyl-4-cyclohexenyl-1)methyl Number litter Mean value da number rats pregnancy occur-rid D l'adamantoate of clalm Dose Expem Exp 2.; 5. [2-methyl-3-ethyl 4 (p-anisyl)-4-cyclohexenyl-1] Example mgJkg. Control mental Control mental tated 60 methyl badamantoate of claim 0.1 10 10 7 10 10.3 14.7 35 H 0.25 1515 4510 4.4 as 6. Compounds of 01am 1 wherein R is cyclopentyl 33 532% 3%2333312311231311: 15.90 lower alkyl of p to 3 carbon atoms in the alkyl portion. In M 10m 9/10 mg m 27 7. [2-methyl-3-ethyl 4 (p-amsyl)-3-cyclohexenyl-1] L 10/10 /10 m3 5 methyl-fi-cyclopentylpropionate of claim 6. W 0 .1 *2/12 142 2-2 a 1 0. 5 W16 W16 15 No references cited. XIIIA 0.5 /20 /20 4.7 1.0 3%4 LORRAINE A. WEINBERGER, Primary Examiner 1.0 16/20 16/20 4.7 7.1 33-62 .5 1 -0 90 R.GERSTL,Ass1stant-Exam1ner 5.0 10/10 0/10 15 xrn 0. US. Cl. X.R.

XIV 0.1 10/10 10/10 10.3 8.9 27 

